Prostatitis and prostatodynia are extremely prevalent diseases in men (Collins M M, et al., "How common is prostatitis? A national survey of physician visits," Journal of Urology, 159:1224-1228 (1998)). There are more outpatient visits for prostatitis than for benign prostatic hypertrophy (BPH) or prostate cancer. Although the epidemiologic evidence is limited, it appears that the prevalence of prostatitis is approximately 2-9% in adult men. It has been suggested that 35-50% of men are affected by prostatitis at some time in life. Based on the National Ambulatory Medical Care Surveys from 1990-1994, approximately 2 million ambulatory visits are made annually for prostatitis. This accounts for 8% of all visits to urologists and 1% of all visits to primary care physicians. Many men remain symptomatic for much of their lives.
This category of poorly understood syndromes is characterized by evidence of prostatic inflammation and by the presence or absence of white blood cells in prostatic fluid and/or pain associated with the prostate. Within this group of syndromes, the origins of chronic idiopathic prostatitis, asymptomatic prostatitis, and prostatodynia are problematic and are probably the least understood. The origin of these diseases have been attributed to some undefinable bacterial or viral infection, but this has never been proven. These syndromes do not exist prior to puberty but have a peak incidence between the ages of 18 and 50. It is possible that these three specific entities actually represent the same disease process in different phases or forms. Suggestions as to the origins of these conditions have included a chemical imbalance in the prostate, infection undetected by current microbiological methods, and autoimmunity to the prostate gland itself.
Chronic nonbacterial prostatitis is an inflammatory and pain condition of unknown etiology characterized by excessive inflammatory cells in prostatic secretions despite no history of documented urinary tract infection and negative bacterial cultures of urine and prostatic secretions. Chronic nonbacterial prostatitis is even more common than bacterial prostatitis. Symptoms simulate those of chronic bacterial prostatitis and these patients usually show an increase in the number of white blood cellss and oval fat bodies in their expressed prostatic secretions. However, they rarely have a history of urinary tract infection, and lower-tract localization cultures fail to reveal a pathogenic organism. Patients with prostatodynia have negative bacterial cultures, normal prostatic secretions, and no history of urinary tract infection. Symptoms of chronic nonbacterial prostatitis and prostatodynia vary but include urinary urgency and frequency, nocturia, dysuria, and pain and discomfort perceived in the pelvic, suprapubic, or genital area. Sometimes postejaculatory pain and discomfort are prominent features. Physical findings for both conditions are nonspecific.
Currently, there are no established treatments for chronic nonbacterial prostatitis or prostatodynia. Antibiotics are often prescribed empirically, but with little evidence of efficacy. Alpha blockers are sometimes prescribed for prostatodynia, but their efficacy has not been established. Patients who respond poorly to medical management or have significant emotional problems are referred for psychiatric intervention. Hot sitz baths and anticholinergic drugs are genearlly employed to provide some symptomatic relief, as is periodic prostatic massage.
Although the present invention is not limited to a specific mechanism of action, the inventors postulate that a neurokinin-1 antagonists would be effective in the treatment of chronic nonbacterial prostatitis or prostatodynia by affecting inflammatory and pain mechanisms in the prostate. In accodance with the present invention, administration of a neurokinin-1 receptor antagonist would reduce both the inflammation and pain that characterize chronic nonbacterial prostatitis and prostatodynia. Furthermore, the effects of the neurokinin-1 receptor antagonist on smooth muscle in the bladder and urethra would also have beneficial effects on the urinary symptoms of prostatitis and prostatodynia. Accordingly, a tacykinin antagonist, in particular a neurokinin-1 receptor antagonist would be useful in the treatment or prevention of chronic nonbacterial prostatitis or prostatodynia.
The neuropeptide receptors for substance P (neurokinin-1; NK-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev., 1983, 3, 85-141). The NK-1 and NK-2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci., 42, 1295-1305 (1988)).
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence. In addition to SP the known mammalian tachykinins include neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1, neurokinin-2, and neurokinin-3, respectively.
Substance P is a pharmacologically-active neuropeptide that is produced in mammals and acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R. C. A. Frederickson et al., Science, 199, 1359 (1978); P. Oehme et al., Science, 208, 305 (1980)) and plays a role in sensory transmission and pain perception (T. M. Jessell, Advan. Biochem. Psychopharmacol. 28 189 (1981)).
Conditions in which substance P has been implicated include disorders of bladder function, such as cystitis, bladder detrusor hyperreflexia, and urinary incontinence (see PCT International Patent Publication No. WO 95/16679 and EPO Patent Publication No. EP 0,610,021). It has been suggested that substance P is implicated in certain urinary tract conditions (Chapple C R, et al., Journal of Urology, 146:1637-1644 (1991); Danuser H, et al., Journal of Urology, 157:1018-1024 (1997); Palea S, et al., Journal of Pharmacology and Experimental Therapeutics 277:700-705 (1996); Tainio H, Acta. Histochem., 97:113-119 (1995)). It has also been suggested that neurokinin-2 receptor antagonists might be useful for treatment of urinary bladder disorders and interstitial cystitis (Palea S, et al., "Pharmacological characterization of tachykinin NK2 receptors on isolated human urinary bladder, prostatic urethra, and prostate," Journal of Pharmacology and Experimental Therapeutics, 277:700-705 (1996)). Prior to the present invention, however, it has not been disclosed or suggested that a neurokinin-1 receptor antagonist would be useful for the treatment of chronic nonbacterial prostatitis or prostatodynia. Currently there are only limited means for treating or preventing chronic nonbacterial prostatitis or prostatodynia. In view of the short-comings of existing agents, there is a need for new effective methods for treating or preventing chronic nonbacterial prostatitis or prostatodynia.